We found a very high prevalence of Alzheimer disease (AD) (20% of those 60 years or older) in an inbred Arab community in northern Israel. This observation is apparently unrelated to the APOE c4 allele which has a frequency of <4% in demented and non-demented elders. A low resolution genome scan and fine mapping studies uncovered AD susceptibility loci in several chromosomal regions that have been implicated in previous studies of outbred Caucasian populations. We also found association between AD and several single nucleotide polymorphisms (SNPs) in the angiotensin converting enzyme gene on chromosome 17. During our investigation of the genetic etiology of AD in this community, we discovered coincidentally a very high prevalence of hypertension which was associated with AD. Going forward, the primary focus of our project remains the genetic basis of AD. In light of emerging evidence for a vascular component to AD risk, we plan to expand the scope of the study to investigate genetic pathways for hypertension, and more specifically, the relationship between the two disorders in this population. To accomplish these goals, we will screen all persons residing in this community ages 65 and older (approximately 2,163) for dementia, and will obtain from a carefully selected subset of 750 cohort members (including 150 subjects meeting AD criteria, 150 subjects with essential hypertension, 150 subjects with both AD and hypertension, and 300 non demented, normotensivc controls) risk factor data and blood samples for biochemical and DNA studies and for establishing lymphoblastoid cell lines. Our scientific aims are: 1) Identify 100,000 base pair regions containing AD (and possibly hypertension) susceptibility genes on chromosomes 9, 10, 12 and 17 by profiling 600 SNPs spanning 15 million base pairs in each of the four previously implicated chromosomal regions using high throughput genotyping technology; and evaluate these data using allelic and haplotype association methods; 2) Fine-map disease loci in the 100 kb regions showing significant association in Aim 1 using a grid of SNPs in 20 kb intervals, and repeating this process iteratively with a higher density of SNPs until the maximum linkage disequilibrium is attained; 3) Evaluate association between disease and 50 genes within the intervals showing the strongest signals in Aim 2 by genotyping additional SNPs and sequencing as necessary; 4) Evaluate association between disease and 100 genes with an emphasis on genes previously implicated in AD and genes involved in vascular functioning; and 5) Determine the relative contributions of SNPs showing significant association to disease susceptibility and investigate interactions among SNPs from multiple loci and with other factors including plasma homocysteine levels and education. The ultimate goal of this study is to find new targets (genetic and non-genetic) for therapy.